Abstract Glioma is a highly lethal malignancy with unknown etiology that accounts for nearly 80% of adult malignant brain tumors. The aims of this project are to conduct an exploratory investigation of the relationship of methylmercury (MeHg) exposure with glioma risk and survival. MeHg is a potent neurotoxin associated with adverse effects on neurologic function both in adults and in children exposed prenatally. MeHg is a ubiquitous environmental contaminant with fish and shellfish consumption comprising the major source of exposure. The central nervous system is highly susceptible to the toxic effects of MeHg since the compound is able to cross the blood-brain barrier and accumulates in neural astrocytes, the cells in the brain which give rise to glioma. MeHg has been suggested to trigger the overproduction of reactive oxygen species causing oxidative stress and subsequent cellular damage. There is also evidence that MeHg inhibits the antioxidant effects of glutathione and selenoproteins, enzymes which mediate most of the antioxidant functions of selenium. The project will be based on a multicenter NCI-funded (R01 CA116174) case-control study exploring genetic and environmental risk factors for adult glioma underway at major medical centers in the Southeastern US. Nail clippings to measure levels of trace elements and oral DNA samples to study genetic susceptibility are available for all study participants. Given the high variability o MeHg content in fish and individual differences in mercury metabolism, measuring MeHg levels in nail clippings will provide a more accurate measurement of MeHg exposure than dietary assessment. Specific aims of this project are to: 1) Measure toenail MeHg in 250 incident glioma cases and 250 matched community controls; 2) Genotype functional or tagging single nucleotide polymorphisms in 1200 cases and 1200 controls for genes involved in the transport (SLC7A8, SLC7A5, SLC11A2), biotransformation (GCLC, GCLM), distribution (MT1A, MT1M, MT2A, MT4, MTF1), and elimination (MRP1, MRP2) of MeHg; and 3) Evaluate associations of toenail MeHg and mercury metabolism genotypes with glioma risk and patient outcome. To our knowledge this will be the first population study to investigate MeHg exposure as a potential glioma risk factor and to evaluate genetic variation in mercury metabolism with glioma. Based on a large, nearly completed case-control study, the proposed pilot investigation may provide new information on a potential environmental risk factor, mechanisms for glioma tumor development, and directions for future study.